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Indomethacin is a widely used non-steroidal anti-inflammatory drug (NSAID) and extensively employed for treatment of arthritis. Delayed action (at the morning or night) is needed for arthritic patients. To improve the patient compliance, in this study we aimed to delay the drug release by designing multi-particulates system in the form of microspheres, which would efficiently release the drug into the colon and replace the conventional therapy. The aim of the present work was to elucidate the effect of formulation variables e.g., amount of eudragit polymer (X1), surfactant concentration (X2) and agitation speed (X3) on in-vitro release profiles (Y1-Y3), drug entrapment efficiency (Y4) and particle size (Y5) of multi-particulates system of indomethacin. Experiments were designed according to a three levels face centered central composite design. Microspheres were formulated with the combination of ethyl cellulose (EC) and Eudragit RS 100/Eudragit S100; by using a novel quasi emulsion solvent diffusion technique. Developed formulations were characterized and evaluated on the basis of FTIR, thermal, particle size, SEM, XRD analysis and drug release kinetics studies. The formulation variables were optimized by response surface methodology (RSM). It was found that in-vitro release (Y1-Y3) was decreased significantly (p